Project Summary. Sensory networks continuously fine-tune how they process information to meet ongoing physiological demands. The nervous system achieves this flexibility via the release of ?neuromodulators? which alter the biophysical and synaptic properties of individual neuron classes within a network. This adjusts the influence of each class to optimize network dynamics for the appropriate context. Neuromodulation is ubiquitous and many neurological disorders result from, or are associated with, dysfunctional neuromodulatory systems. Despite the importance of neuromodulation for healthy sensory processing, our ability to predict the consequences of neuromodulation is limited by the diversity of modulatory receptors expressed by different classes of neurons. Each receptor has different effects and each class of neuron supports different features of sensory coding, so the effects of neuromodulation can be complex. We propose to address this issue in a genetically tractable model with fewer neurons and modulatory receptors; the olfactory system of Drosophila. The objective of this application is to determine how serotonin (5-HT) receptor subtypes affect key neuronal classes and the consequences for olfactory processing and odor-guided behavior. The long-term goal of this research is to determine the mechanistic basis for neuromodulation of sensory network dynamics. In vertebrate and invertebrate olfactory systems, the effects of 5-HT on odor-evoked responses vary across different neuron classes. However, it is difficult to determine how 5-HT alters olfactory processing without knowing the consequences of activating the 5-HT receptors expressed by each class. We recently completed a comprehensive atlas of 5-HT receptor expression within the olfactory system, so we now propose to manipulate the expression of individual 5-HT receptors in specific classes of neurons to determine how 5-HT affects individual neuron classes, the consequences for odor coding across olfactory brain regions and odor- guided behavior. In addition, we will use one of the first whole brain, nanometer resolution EM connectomes to establish single cell resolution connectivity rules of 5-HT neurons with each olfactory neuron class examined in this proposal. In Specific Aim 1 we will determine the receptor basis for the effects of 5-HT on local inhibitory networks within the first olfactory neuropil (the antennal lobe or ?AL?). In Aim 2 we will determine the contribution of direct modulation of cholinergic AL output neurons to the overall effects of 5-HT on olfactory information sent to downstream processing stages. Finally, in Aim 3 we will determine how 5-HT receptors modulate GABAergic AL output neurons that promote olfactory attraction. These experiments will establish how the overall effects of 5-HT emerge from neuron class-specific expression of 5-HT receptors, thus addressing a critical gap in our knowledge of healthy sensory processing.